Hepcidin induces HIV-1 transcription inhibited by ferroportin

Abstract

BackgroundPhysiological regulation of cellular iron involves iron export by the membrane protein, ferroportin, the expression of which is induced by iron and negatively modulated by hepcidin. We previously showed that iron chelation is associated with decreased HIV-1 transcription. We hypothesized that increased iron export by ferroportin might be associated with decreased HIV-1 transcription, and degradation of ferroportin by hepcidin might in turn induce HIV-1 transcription and replication. Here, we analyzed the effect of ferroportin and hepcidin on HIV-1 transcription.ResultsExpression of ferroportin was associated with reduced HIV-1 transcription in 293T cells and addition of hepcidin to ferroportin-expressing cells counteracted this effect. Furthermore, exposure of promonocytic THP-1 cells to hepcidin was associated with decreased ferroportin expression, increased intracellular iron and induction of reporter luciferase gene expression. Finally, exposure of human primary macrophages and CD4+ T cells to hepcidin and iron was also associated with induction of viral production.ConclusionOur results suggest that the interplay between ferroportin-mediated iron export and hepcidin-mediated degradation of ferroportin might play a role in the regulation of HIV-1 transcription and may be important for understanding of HIV-1 pathogenesis.

Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections

“…HIV-1 replication requires cellular iron (27), and hepcidin, which causes cellular iron retention, enhances HIV-1 replication in vitro (28). Therefore, we considered whether hepcidin levels measured during early infection might predict later set-point plasma viral load, which is established following acute and early events and is a strong prognostic indicator for disease progression (29,30).…”

“…Hepcidin downregulates surface expression of ferroportin in both lymphocytes and macrophages (36,37), increasing iron availability in key cellular sites of HIV-1 replication. HIV-1 replication is iron dependent (27); accordingly, HIV-1 replication is enhanced, in parallel with decreased ferroportin and increased cellular iron following treatment of promonocytic THP1 cells, primary human macrophages, and primary CD4+ lymphocytes with hepcidin (28). Thus, elevated hepcidin, as well as reflecting inflammation, may also contribute to a cellular environment favoring HIV-1 replication.…”

Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin

“…First, we examined the effect of hepcidin on ferroportin Q248H expression in human embryonic kidney 293T cells that naturally express undetectable levels of ferroportin. 34 Cells were transiently transfected with plasmids expressing ferroportin Q248H, WT ferroportin or ferroportin C326Y, a mutant that is not sensitive to hepcidin. 34 The EGFP expression plasmid was Figure 1A, lanes 6, 7 and 8), ferroportin Q248H expression persisted following treatment with 0.01 and 0.03 mM hepcidin ( Figure 1A, lanes 2 and 3) and was only reduced by treatment with 0.1 mM hepcidin ( Figure 1A, lane 4).…”

“…34 Cells were transiently transfected with plasmids expressing ferroportin Q248H, WT ferroportin or ferroportin C326Y, a mutant that is not sensitive to hepcidin. 34 The EGFP expression plasmid was Figure 1A, lanes 6, 7 and 8), ferroportin Q248H expression persisted following treatment with 0.01 and 0.03 mM hepcidin ( Figure 1A, lanes 2 and 3) and was only reduced by treatment with 0.1 mM hepcidin ( Figure 1A, lane 4). In contrast, ferroportin C326Y expression persisted at all hepcidin concentrations with a slight reduction when hepcidin was added (Figure1A, lanes 10-12).…”

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

“…[7][8][9] In vitro studies also provided conflicting evidence linking iron with HIV progression. Higher cellular iron levels in HIV-infected macrophages are associated with increasing HIV transcription, 10,11 and treatment of monocytes with the iron chelator deferoxamine (DFO) decreased NF-jB and HIV-1 reactivation by oxidative stress. 12 However, another study found no change in NF-jB with iron chelation.…”